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Outrage of the Month: Unethical Human Experimentation in 2015 and Our Broken System for Protecting Human Research Subjects

Health Letter, December 2015

Michael Carome, M.D.

From 1946 to 1948, the U.S. Public Health Service (USPHS) conducted highly unethical medical research in Guatemala.[1] Some of the research involved deliberately infecting people with sexually transmitted diseases (STDs), such as syphilis and gonorrhea, without their consent.[2] In 2011, the Presidential Commission for the Study of Bioethical Issues concluded, "It is clear that many of the actions undertaken within the Guatemala experiments were morally wrong."[3]

Many people believe that such government-funded research could never take place again. But disturbingly, morally wrong human experimentation continues to occur today. The most recent examples are the iCOMPARE and FIRST clinical trials, which are intended to test whether excessively long work-hour schedules for medical residents at hospitals across the U.S. cause more death and injuries to patients.

The regulations require that most federally funded human research be reviewed and approved by a committee called an institutional review board (IRB) before the research begins. In reviewing research, IRBs must ensure that risks to subjects will be minimized and will be reasonable in relation to any potential benefits to the subjects and the importance of the scientific knowledge expected to result. The regulations also require that researchers obtain and document the voluntary informed consent of all subjects, except in limited circumstances involving low-risk research.

Despite these federal regulations, highly unethical human research continues to occur. While perhaps not as obviously abhorrent as the STD research in Guatemala, the iCOMPARE and FIRST trials share a common theme with those 1940s studies: Researchers are deliberately exposing human subjects to an experimental procedure already known to be harmful, without their consent.

The iCOMPARE and FIRST trials have allowed first-year medical residents to work shifts lasting 28 consecutive hours or more — nearly twice the current maximum number of hours allowed by the Accreditation Council for Graduate Medical Education (ACGME) for such residents. The ACGME's awareness of the known harms to both residents and patients caused by excessively long work hours led the organization in 2011 to tighten restrictions on resident physicians' work hours, including limiting shifts for first-year residents to a maximum of 16 hours.

Substantial evidence shows that sleep deprivation due to excessively long work shifts increases the risk of motor vehicle accidents,[4],[5],[6] needle-stick injuries and exposure to blood-borne pathogens,[7],[8] and depression in medical residents.[9],[10] It also exposes their patients to an increased risk of medical errors, sometimes leading to patient injuries and deaths.

The iCOMPARE trial, which started on July 1, 2015, and is ongoing, is funded in part by the National Institutes of Health and involves internal medicine residents at 63 institutions and their affiliated hospitals. The FIRST trial, which ran from July 1, 2014, until June 30, 2015, took place at approximately 160 hospitals and involved general surgery residents.

The primary goal of the two trials is to determine whether the rates of death and serious complications for the unwitting patients at the hospitals where first-year residents are forced to work significantly longer work shifts (28 or more hours) are higher than the rates of death and serious complications in patients enrolled at hospitals where first-year residents’ work shifts comply with the ACGME limit of 16 consecutive hours.

Among the many disturbing aspects of the trials is the researchers’ failure to seek the voluntary informed consent of either the resident doctors or their patients who are forced to be part of these experiments.

According to a recent media report, the University of Pennsylvania's IRB — the designated lead IRB that reviewed and approved the iCOMPARE trial — incorrectly found that the trial involves only "minimal" risk and therefore waived the requirements for obtaining informed consent for all subjects.

For the FIRST trial, the administrator of the IRB at Northwestern University, the lead institution for that trial, shockingly determined that the trial was not even "research with human subjects" and, therefore, that IRB review and approval were not required. As a result, there was no opportunity for the IRB to discuss the risks of the research and the need for obtaining the voluntary informed consent of both the general surgery residents and their patients. This determination represents a colossal failure of Northwestern University's human subjects protection system. This same failure presumably occurred at many of the other institutions that participated in the FIRST trial.

It seems highly unlikely that a trial that involves randomizing medical residents to a duty-hour schedule with longer shifts and less time off between shifts could ever be designed and conducted in a manner that would satisfy basic ethical principles or the federal human subjects protection regulations. The fact that so many prestigious academic institutions allowed the iCOMPARE and FIRST trials to proceed as proposed by the researchers indicates serious, widespread breakdowns in our nation’s system for protecting human subjects.

Most importantly, OHRP and other federal agencies need to figure out how these failures could have happened in the first place and implement reforms to minimize the possibility that such morally wrong human experimentation occurs again.